1. Field of the Invention
This invention focuses on the administration of dispersions of certain lyotropic liquid crystal compositions to attenuate the toxic or medically undesirable effect of one or more compounds present in the body of a human or other mammal. The particles in dispersion comprise reversed cubic phase and/or reversed hexagonal phase liquid crystalline material in which a toxin or a drug substance is soluble and partitions substantially. The particle dispersions are suitable for administration to a human, and are given preferably by injection, most preferably intravenously, in an amount sufficient to be effective in attenuating the effects of a toxin or therapeutic drug in the body. The attenuation of the effects of toxins or drug substances in the body may result from sequestering the toxin or therapeutic drug from the plasma, displacing the toxin from the site of action, inducing redistribution of the toxin, or by other mechanisms. Adjusting the composition by various means may increase or decrease the absorption or adsorption of a toxin or drug substance to the particles, the rate of uptake of the particles and associated toxins or drug substances by the liver, and otherwise impact attenuation of the effects of a toxin or drug substance. The invention is especially applicable in reversing adverse effects of local anesthetics delivered systemically, and attenuating the therapeutic effects of general anesthetics in the course of treatment.
2. Background of the Invention
In most clinical applications, local anesthetics are typically injected or applied at or near a site intended to render an area or region of the body insensate to painful stimuli. Once applied or administered, systemic absorption of the local anesthetic occurs or, in some instances, a portion of the injectate may be inadvertently administered directly into the vascular system. In any case, local anesthetics may exert varying degrees of systemic toxicity. Toxicity is usually directly proportional to the potency of the local anesthetic administered. It is widely believed that most local anesthetics exert their effects by binding to the alpha-subunit and blocking the voltage-gated sodium channel from an intracellular location, thereby conformationally inactivating the sodium channel and disrupting the influx of sodium ions preventing membrane depolarization. Local anesthetics are also known to block calcium, potassium and N-methyl-D-aspartate (NMDA) receptors to varying degrees. These differences are associated with the unique clinical profiles associated with each local anesthetic agent.
The unintentional intravascular administration of local anesthetics, bupivacaine in particular, which can occur during procedures designed to effect regional anesthesia can result in severe cardiac complications. These reactions include marked hypotension, atrioventricular dissociative heart block, idioventricular dysrhythmias as well as ventricular tachycardia and ventricular fibrillation. It is widely accepted that the R+ isomer of bupivacaine has a strong affinity to binding cardiac sodium channels and that its dissociation from this site is very slow. At higher concentrations, calcium and potassium channels can also be blocked, further exacerbating the cardiotoxic effects.
Bupivacaine induced cardiac toxicity is a life-threatening emergency in which aggressive measures must be undertaken to preserve life. These measures frequently involve immediate and repeated administration of vasopressors to maintain normovascular tone as well as other agents to control the bradycardia, complete heart block and the various cardiac dysrhytmias which ensue. Cardiopulmonary resuscitation may be required to maintain oxygenation of vital organs while the myocardium is in arrest. It is not uncommon to attempt to emergently effect extracorporeal oxygenation via cardiopulmonary bypass with membrane oxygenation (or similar device) to await the return of a normalized cardiac cycle once the offending concentration of bupivacaine has been redistributed, metabolized or otherwise inactivated, and allow for the physiologic normalization of the myocardial cycle.
A number of specific therapies for local anesthetic toxicity have been proposed over the years including bretylium, glucose/insulin/potassium infusions, emergent resuscitative efforts (i.e. cardiopulmonary resuscitation CPR), and cardiopulmonary bypass. Recently, attempts have been made to use fatty emulsions, typified by the product marketed under the name Intralipid®, to scavenge bupivacaine and thereby reverse toxic effects. [See, e.g., Weinburg G, Ripper R, Feinstein D L, Hoffman W. RA&PM 2003; 28:198; Weinberg et al. (1998) Anesthesiology 88(4):1071]. Similarly Intralipid® has been investigated for use in ropivacaine toxicity. [Litz et al. (2006) Anaesthesia 61:800]. Tebbutt et al. found increased survival in a rat model of verapamil toxicity. [Tebbutt et al., Acac. Emerg. Med. (2006) 13:134]. Bania, Chu and Stolbach looked at the use of Intralipid® to try to raise the LD50 in mice of an organophosphate compound, paraoxon. [Acad Emerg Med (2005) 12(5 Supplement 1): 12]. The group of Bania and Chu has also looked at the use of Intralipid® to treat toxicities from propanolol, VER, and amitriptyline. [Reported at the 2006 National SAEM Meeting, San Francisco Calif.]. Mathy-Hartert et al. investigated the use of Intralipid® against reactive oxygen species produced by phorbol myristate acetate, but found only a weak effect. [Mathy-Hartert et al., Mediators Inflamm. (1998) 7:327]. Microemulsions made from Pluronic surfactant, ethyl butyrate, fatty acid sodium salts and water have been proposed for scavenging bupivacaine by the group of Dennis et al. [See Dennis et al., U.S. patent application Ser. No. 10/420,608, Varshney et al. (2004) J. Am. Chem. Soc. 126:5108 and Renehan et al. (2005) Reg. Anes. Pain Med. 30(4):380]. Dennis and coworkers have also proposed particles containing detoxifying enzymes, in U.S. Pat. No. 6,977,171.
Intralipid® and related parenteral fatty emulsions have several disadvantages and limitations in the present context. Perhaps most importantly, they rely on triglycerides (soybean oil in Intralipid®, other fats for the other fatty emulsions) for the solubilization and partitioning of compounds into the emulsion droplets, and as such they are strongly limited. Triglycerides are many-fold higher in molecular weight (on the order of 900 Da) than most compounds that are known to be effective solubilizers, as the favorable entropies of mixing associated with low-MW compounds is important for the functioning of most solvents. They are extremely hydrophobic, and thus very poor solvents for compounds that have one, or particularly more than one, polar group. Their propensity to support microbial contamination makes them poorly suited for field applications. And the high levels of polyunsaturated fats in lipid emulsions, combined with low levels of tocopherol to combat oxidation, lead to growing levels of peroxides and other free radical sources that can contribute to toxicities related to reactive oxygen species.
There is a need for a pharmaceutically acceptable composition and method for attenuating the effects of common drugs in circumstances in which they are toxic and in situations in which for other reasons, such as medical treatment or patient management, their attenuation is desirable which can work effectively, against a range of drugs and other toxins, and can be adjusted for different characteristics of action and different toxins.